Design, synthesis, and in vitro antimycobacterial activities of butylene tethered 7‐fluoroisatin‐isatin scaffolds

In this work, a series of butylene tethered heteronuclear 7‐fluoroisatin‐isatin scaffolds 4a to 4h were designed and synthesized, and the antimycobacterial activity profiles, cytotoxicity together with inhibitory activity against MTB DNA gyrase, were also investigated. All the synthesized heteronuclear scaffolds were active against MTB H37Rv and MDR‐MTB strains, and some of them were more potent than isoniazid (INH), rifampicin (RIF), ethambutol (EMB) against MDR‐MTB strain. The structure‐activity relationship demonstrated that the substituents on C‐3 position of 7‐fluoroisatin and isatin moieties were closely related with the activity, and hydrogen bond donors were favorable to the activity. Scaffolds with different substituents showed higher activity than the analogs with the same substituents at this position of the two isatin motifs, which may be attributed to the synergistic effect. Among them, the most active scaffold 4e (MIC: 1 and 4 μg/mL) was comparable with the first‐line anti‐TB agent EMB against MTB H37Rv, and ≥16‐fold more potent than INH, RIF, and EMB against MDR‐MTB strain, demonstrating its potential for fighting against infections caused by both drug‐sensitive and MDR MTB strains. Moreover, scaffold 4e also possessed excellent toxicological profiles and promising inhibitory activity against MTB DNA gyrase. Thus, scaffold 4e could act as an ideal platform for further optimization.